Pathophysiology of chronic fatigue syndrome

The pathogenesis of chronic fatigue syndrome (CFS) is uncertain, but may involve multiple organ and body systems, including neurological, endocrinal and immunological factors.

Nervous system factors

Neurological abnormalities

CFS may involve neurological abnormalities, revealed by MRI and SPECT scans,cite journal |author=Schwartz RB, Garada BM, Komaroff AL, "et al" |title=Detection of intracranial abnormalities in patients with chronic fatigue syndrome: comparison of MR imaging and SPECT |journal=AJR. American journal of roentgenology |volume=162 |issue=4 |pages=935–41 |year=1994 |pmid=8141020 |doi=] blood flow measurements,cite journal |author=Abu-Judeh HH, Levine S, Kumar M, "et al" |title=Comparison of SPET brain perfusion and 18F-FDG brain metabolism in patients with chronic fatigue syndrome |journal=Nuclear medicine communications |volume=19 |issue=11 |pages=1065–71 |year=1998 |pmid=9861623 |doi=] studies of the serotonin signalling pathways,cite journal |author=Demitrack MA, Gold PW, Dale JK, Krahn DD, Kling MA, Straus SE |title=Plasma and cerebrospinal fluid monoamine metabolism in patients with chronic fatigue syndrome: preliminary findings |journal=Biol. Psychiatry |volume=32 |issue=12 |pages=1065–77 |year=1992 |pmid=1282370 |doi=] cite journal |author=Cleare AJ, Messa C, Rabiner EA, Grasby PM |title=Brain 5-HT1A receptor binding in chronic fatigue syndrome measured using positron emission tomography and [11C] WAY-100635 |journal=Biol. Psychiatry |volume=57 |issue=3 |pages=239–46 |year=2005 |pmid=15691524 |doi=10.1016/j.biopsych.2004.10.031] and gene expression.cite journal |author=Goertzel BN, Pennachin C, de Souza Coelho L, Gurbaxani B, Maloney EM, Jones JF |title=Combinations of single nucleotide polymorphisms in neuroendocrine effector and receptor genes predict chronic fatigue syndrome |journal=Pharmacogenomics |volume=7 |issue=3 |pages=475–83 |year=2006 |pmid=16610957 |doi=10.2217/14622416.7.3.475] Levels of beta-endorphin, a natural pain killer, are low in some CFS patients.cite journal |author=Conti F, Pittoni V, Sacerdote P, Priori R, Meroni PL, Valesini G |title=Decreased immunoreactive beta-endorphin in mononuclear leucocytes from patients with chronic fatigue syndrome |journal=Clin. Exp. Rheumatol. |volume=16 |issue=6 |pages=729–32 |year=1998 |pmid=9844768 |doi=] Some of these findings resemble viral infectioncite journal |author=Schwartz RB, Komaroff AL, Garada BM, "et al" |title=SPECT imaging of the brain: comparison of findings in patients with chronic fatigue syndrome, AIDS dementia complex, and major unipolar depression |journal=AJR. American journal of roentgenology |volume=162 |issue=4 |pages=943–51 |year=1994 |pmid=8141022 |doi=] and clinical depression,cite journal |author=MacHale SM, Lawŕie SM, Cavanagh JT, "et al" |title=Cerebral perfusion in chronic fatigue syndrome and depression |journal=The British Journal of Psychiatry : the journal of mental science |volume=176 |issue= |pages=550–6 |year=2000 |pmid=10974961 |doi=] while others do not.

Dysautonomia is the disruption of the function of the autonomic nervous system (ANS) which controls many aspects of homeostasis. In CFS this is mostly orthostatic intolerance - the inability to stand up without feeling dizzy, faint, or nauseated.cite journal |author=Goldstein DS, Robertson D, Esler M, Straus SE, Eisenhofer G |title=Dysautonomias: clinical disorders of the autonomic nervous system |journal=Ann. Intern. Med. |volume=137 |issue=9 |pages=753–63 |year=2002 |pmid=12416949 |doi=] Research on CFS orthostatic intolerance shows associations with nerually mediated hypotension and postural orthostatic tachycardia syndrome,cite journal |author=Galland BC, Jackson PM, Sayers RM, Taylor BJ |title=A matched case control study of orthostatic intolerance in children/adolescents with chronic fatigue syndrome |journal=Pediatr. Res. |volume=63 |issue=2 |pages=196–202 |year=2008 |pmid=18091356 |doi=10.1203/PDR.0b013e31815ed612] [Tolan R, Stewart J. [http://www.emedicine.com/ped/topic2795.htm "Chronic Fatigue Syndrome"] , "eMedicine", August 17 2006, retrieved November 9 2006.] [ Rowe, PC. [http://www.pediatricnetwork.org/medical/OI/johnshopkins.htm "General Information Brochure on Orthostatic Intolerance and its Treatment"] , "Chronic Fatigue Clinic, Johns Hopkins Children's Center", February 2003, retrieved November 9 2006.] as well as hypocapnia.cite journal |author=Natelson BH, Intriligator R, Cherniack NS, Chandler HK, Stewart JM |title=Hypocapnia is a biological marker for orthostatic intolerance in some patients with chronic fatigue syndrome |journal=Dyn Med |volume=6 |issue= |pages=2 |year=2007 |pmid=17263876 |doi=10.1186/1476-5918-6-2] These conditions may cause blood to pool in the lower body when a person stands, reducing blood flow to the heart and brain. Many CFS patients report symptoms of orthostatic intolerance and low or lowered blood pressure. [cite journal |author=Newton JL, Okonkwo O, Sutcliffe K, Seth A, Shin J, Jones DE |title=Symptoms of autonomic dysfunction in chronic fatigue syndrome |journal=QJM |volume=100 |issue=8 |pages=519–26 |year=2007 |pmid=17617647 |doi=10.1093/qjmed/hcm057] cite journal |author=Stewart JM, Gewitz MH, Weldon A, Arlievsky N, Li K, Munoz J |title=Orthostatic intolerance in adolescent chronic fatigue syndrome |journal=Pediatrics |volume=103 |issue=1 |pages=116–21 |year=1999 |pmid=9917448 |doi=]

Depression and other psychiatric disorders

CFS symptoms are often attributed to clinical depression; there are clinical overlaps and differences between the two. Depression occurs in 10-15% of CFS patients.Stein E (2001), "How to differentiate CFS from Psychiatric Disorder", Presented at The Alison Hunter Memorial Foundation Third International Clinical and Scientific Conference, Sydney, Australia] Previous psychiatric disorders or shared risk factors for psychiatric disorders may have an etiological role in some cases of CFS.cite journal |author=Harvey SB, Wadsworth M, Wessely S, Hotopf M |title=The relationship between prior psychiatric disorder and chronic fatigue: evidence from a national birth cohort study |journal=Psychol Med |volume= |issue= |pages=1-8 |year=2007 |pmid=17976252 |doi=10.1017/S0033291707001900] The presence of multiple comorbid disorders could be a marker for psychological influences on etiology.cite journal |author=Whitehead WE, Palsson O, Jones KR |title=Systematic review of the comorbidity of irritable bowel syndrome with other disorders: what are the causes and implications? |journal=Gastroenterology |volume=122 |issue=4 |pages=1140-56 |year=2002 |pmid=11910364 |doi=] Neuropsychological impairments could be involved in CFS,cite journal |author=Deluca J, Johnson SK, Natelson BH |title=Neuropsychiatric status of patients with chronic fatigue syndrome: an overview |journal=Toxicol Ind Health |volume=10 |issue=4-5 |pages=513-22 |year=1994 |pmid=7778111 |doi=] and neuroendocrine studies and brain imaging have confirmed the occurrence of neurobiological abnormalities in most patients with CFS. cite journal |author=Gonzalez MB, Cousins JC, Doraiswamy PM |title=Neurobiology of chronic fatigue syndrome |journal=Prog. Neuropsychopharmacol. Biol. Psychiatry |volume=20 |issue=5 |pages=749-59 |year=1996 |pmid=8870062 |doi=]

Findings of increased autoimmune antibodies against phosholipids (phosphatidyl inositol) in CFS and depression may underpin the similarities and comorbity between the two disorders.cite journal |author=Maes M, Mihaylova I, Leunis JC |title=Increased serum IgM antibodies directed against phosphatidyl inositol (Pi) in chronic fatigue syndrome (CFS) and major depression: evidence that an IgM-mediated immune response against Pi is one factor underpinning the comorbidity between both CFS and depression |journal=Neuro Endocrinol. Lett. |volume=28 |issue=6 |pages=861-7 |year=2007 |pmid=18063934 |doi=]

; PsychosocialCentral sensitization could be responsible for the sustaining pain complaints in CFS. This hypothesis is based on the hyperalgesia and allodynia reported in CFS, on the elevated concentrations of nitric oxide presented in the blood of CFS patients, on the typical personality styles seen in CFS and on the brain abnormalities shown on brain images.cite journal |author=Meeus M, Nijs J |title=Central sensitization: a biopsychosocial explanation for chronic widespread pain in patients with fibromyalgia and chronic fatigue syndrome |journal=Clin. Rheumatol. |volume=26 |issue=4 |pages=465-73 |year=2007 |pmid=17115100 |doi=10.1007/s10067-006-0433-9] cite journal |author=Nijs J, Van de Velde B, De Meirleir K |title=Pain in patients with chronic fatigue syndrome: does nitric oxide trigger central sensitisation? |journal=Med. Hypotheses |volume=64 |issue=3 |pages=558-62 |year=2005 |pmid=15617866 |doi=10.1016/j.mehy.2004.07.037]

; BehavioralHigh levels of "action-proneness" may play a predisposing, initiating and/or perpetuating role in CFS.cite journal |author=Van Houdenhove B, Neerinckx E, Onghena P, Lysens R, Vertommen H |title=Premorbid "overactive" lifestyle in chronic fatigue syndrome and fibromyalgia. An etiological factor or proof of good citizenship? |journal=J Psychosom Res |volume=51 |issue=4 |pages=571-6 |year=2001 |pmid=11595245 |doi=] cite journal |author=Van Houdenhove B, Onghena P, Neerinckx E, Hellin J |title=Does high 'action-proneness' make people more vulnerable to chronic fatigue syndrome? A controlled psychometric study |journal=J Psychosom Res |volume=39 |issue=5 |pages=633-40 |year=1995 |pmid=7490698 |doi=] It has been hypothesized that in CFS the health threat is no longer the illness, but rather anything that threatens to disrupt a precarious accommodation to it. Due to established vicious circles, attempts at threat regulation may become inadvertently self-defeating, promoting the threats they attempt to diminish.cite journal |author=Deary V |title=A precarious balance: Using a self-regulation model to conceptualize and treat chronic fatigue syndrome |journal=Br J Health Psychol |volume= |issue= |pages= |year=2008 |pmid=18267050 |doi=10.1348/135910708X283760] In one study, CFS patients were found to have consulted their GP more frequently in the 15 years before development of their condition, for a wide variety of complaints, supporting a hypothesis that behavioural factors might have a role in the etiology of CFS. cite journal |author=Hamilton WT, Hall GH, Round AP |title=Frequency of attendance in general practice and symptoms before development of chronic fatigue syndrome: a case-control study |journal=Br J Gen Pract |volume=51 |issue=468 |pages=553-8 |year=2001 |pmid=11462315 |doi=]

tress and trauma

The majority of people who experience stress or trauma do not develop CFS, but these factors may increase the likelihood of acquiring CFS. [cite journal | author = Hatcher S, House A | title = Life events, difficulties and dilemmas in the onset of chronic fatigue syndrome: a case-control study. | journal = Psychol Med | volume = 33 | issue = 7 | pages = 1185–92 | year = 2003 | pmid= 14580073 | doi = 10.1017/S0033291703008274 | unused_data = |url: http://eprints.whiterose.ac.uk/1226/1/house3.pdf] cite journal | author = Theorell T, Blomkvist V, Lindh G, Evengard B | title = Critical life events, infections, and symptoms during the year preceding chronic fatigue syndrome (CFS): an examination of CFS patients and subjects with a nonspecific life crisis. | journal = Psychosom Med. | volume = 61 | issue = 3 | pages = 304–10 | pmid= 10367610] cite journal | author = Salit IE | title = Precipitating factors for the chronic fatigue syndrome. | journal = J Psychiatr Res | volume = 31 | issue = 1 | pages = 59–65 | year = 1997 | pmid= 9201648 | doi = 10.1016/S0022-3956(96)00050-7 ] Self-reported childhood stress or trauma increases the likelihood of acquiring CFS as an adult. [cite journal | author = Heim C, Wagner D, Maloney E, Papanicolaou DA, Solomon L, Jones JF, Unger ER, Reeves WC | title = Early adverse experience and risk for chronic fatigue syndrome: results from a population-based study. | journal = Arch Gen Psychiatry | volume = 63 | issue = 11 | pages = 1258–66 | year = 2006 | pmid = 17088506 | doi = 10.1001/archpsyc.63.11.1258] A study of twins found both stress and genetics could contribute to CFS, [cite journal | author = Kato K, Sullivan PF, Evengard B, Pedersen NL | title = Premorbid predictors of chronic fatigue. | journal = Arch Gen Psychiatry | volume = 63 | issue = 11 | pages = 1267–72 | year = 2006 | pmid = 17088507 | url = http://archpsyc.ama-assn.org/cgi/content/full/63/11/1267 | doi = 10.1001/archpsyc.63.11.1267] and anxiety disorders have been associated with CFS in 5-15 year olds.cite journal | author = T Chalder, R Goodman, S Wessely, M Hotopf, H Meltzer | title = Epidemiology of chronic fatigue syndrome and self reported myalgic encephalomyelitis in 5-15 year olds: cross sectional study. | journal = BMJ | volume = 327 | pages = 654–655 | year = 2003 | doi = 10.1136/bmj.327.7416.654 | url = http://www.bmj.com/cgi/content/full/327/7416/654] CDC studies found gene mutation and abnormal gene activity levels in CFS patients that may relate to the function of the hypothalamus-pituitary-adrenal (HPA) axis, which helps regulate the body's stress response.cite web | last = Reeves W | coauthors = Vernon S | title = Press Briefing on Chronic Fatigue Syndrome | publisher = Centers for Disease Control and Prevention | date = April 20, 2006 | url = http://www.cdc.gov/od/oc/media/transcripts/t060420.htm | format = HTM | accessdate = 2008-01-27]

Psychoneuroimmunological interactions

The brain and immune system influence each other, especially in the HPA axis and sympathetic nervous system. Mental stress causes suppression of the immune system by hormones such as cortisol and epinepherine. Release of stress hormones, caused by diseases outside the brain, can result in neurological symptoms due to the influence of stress hormones on neurotransmitters. Neuropsychiatric disorders present in CFS may be related to autoantibodies to neuronal or endothelial (interior surface of blood vessels) targets, [cite journal | author = Margutti P, Delunardo F, Ortona E | title = Autoantibodies associated with psychiatric disorders. | journal = Curr Neurovasc Res | volume = 3 | issue = 2 | pages =149–57 | year = 2006 | pmid = 16719797 | doi = 10.2174/156720206776875894] [cite journal | author = Tanaka S, Kuratsune H, Hidaka Y, Hakariya Y, Tatsumi KI, Takano T, Kanakura Y, Amino N | title = Autoantibodies against muscarinic cholinergic receptor in chronic fatigue syndrome. | journal = Int J Mol Med | volume = 12 | issue = 2 | pages = 225–30 | year = 2003 | pmid = 12851722] or disordered cytokine production by glial cells within the central nervous system. [cite journal | author = Vollmer-Conna U, Lloyd A, Hickie I, Wakefield D | title = Chronic fatigue syndrome: an immunological perspective. | journal = Aust N Z J Psychiatry | volume = 32 | issue = 4 | pages = 523–7 | year = 1998 | pmid = 9711366]

Infections

Viral and bacterial infections have been associated with CFS but their influence on etiology and pathophysiology is controversial. Some researchers say there is a higher winter onset of CFS, and their hypothesis is that symptom onset is precipitated by a viral infection in some people.cite journal |author=Jason LA, Taylor RR, Carrico AW |title=A community-based study of seasonal variation in the onset of chronic fatigue syndrome and idiopathic chronic fatigue |journal=Chronobiol. Int. |volume=18 |issue=2 |pages=315-9 |year=2001 |pmid=11379670 |doi=] cite journal |author=Zhang QW, Natelson BH, Ottenweller JE, "et al" |title=Chronic fatigue syndrome beginning suddenly occurs seasonally over the year |journal=Chronobiol. Int. |volume=17 |issue=1 |pages=95-9 |year=2000 |pmid=10672437 |doi=] Other experts say while symptoms of CFS can occur after severe infection, no convincing data exist to support an infectious process in disease maintenance.cite journal |author=Natelson BH, Lange G |title=A status report on chronic fatigue syndrome |journal=Environ. Health Perspect. |volume=110 Suppl 4 |issue= |pages=673-7 |year=2002 |pmid=12194905 |doi=]

Enteroviruses like the Coxsackie virusRamsay MA (1986), "Postviral Fatigue Syndrome. The saga of Royal Free disease", Londen, ISBN 0-906923-96-4] and Polio virus have been associated with symptoms resembling CFS. The validity and implications of enterovirus findings are controversial.cite journal |author=Dalakas MC |title=Enteroviruses in chronic fatigue syndrome: "now you see them, now you don't" |journal=J. Neurol. Neurosurg. Psychiatr. |volume=74 |issue=10 |pages=1361–2 |year=2003 |month=October |pmid=14570825 |doi= |url=http://jnnp.bmj.com/cgi/pmidlookup?view=long&pmid=14570825] Epstein-Barr virus (EBV) is present in 90% of the general population and sometimes causes infectious mononucleosis (glandular fever). EBV was once the principal suspect in chronic fatigue illnesses,cite journal | author = Jones J, Ray C, Minnich L, Hicks M, Kibler R, Lucas D | title = Evidence for active Epstein-Barr virus infection in patients with persistent, unexplained illnesses: elevated anti-early antigen antibodies. | journal = Ann Intern Med | volume = 102 | issue = 1 | pages = 1–7 | year = 1985 | pmid = 2578266] cite journal | author = Straus S, Tosato G, Armstrong G, Lawley T, Preble O, Henle W, Davey R, Pearson G, Epstein J, Brus I | title = Persisting illness and fatigue in adults with evidence of Epstein-Barr virus infection. | journal = Ann Intern Med | volume = 102 | issue = 1 | pages = 7–16 | year = 1985 | pmid = 2578268] but mixed study resultscite journal |author=Holmes GP, Kaplan JE, Stewart JA, Hunt B, Pinsky PF, Schonberger LB |title=A cluster of patients with a chronic mononucleosis-like syndrome. Is Epstein-Barr virus the cause? |journal=JAMA |volume=257 |issue=17 |pages=2297–302 |year=1987 |pmid=3033337 |doi=] cite journal | author = Kawai K, Kawai A | title = Studies on the relationship between chronic fatigue syndrome and Epstein-Barr virus in Japan. | journal = Intern Med | volume = 31 | issue = 3 | pages = 313–8 | year = 1992 | pmid = 1319246 | doi = 10.2169/internalmedicine.31.313] cite journal | author = Lerner A, Beqaj S, Deeter R, Fitzgerald J | title = IgM serum antibodies to Epstein-Barr virus are uniquely present in a subset of patients with the chronic fatigue syndrome. | journal = "In Vivo" | volume = 18 | issue = 2 | pages = 101–6 | year =2004 | pmid = 15113035] have led to the current view of EBV in some patients as either a post infectious causal factorcite journal |author=Glaser R, Padgett DA, Litsky ML, "et al" |title=Stress-associated changes in the steady-state expression of latent Epstein-Barr virus: implications for chronic fatigue syndrome and cancer |journal=Brain Behav. Immun. |volume=19 |issue=2 |pages=91–103 |year=2005 |month=March |pmid=15664781 |doi=10.1016/j.bbi.2004.09.001 |url=] cite journal |author=Devanur LD, Kerr JR |title=Chronic fatigue syndrome |journal=J. Clin. Virol. |volume=37 |issue=3 |pages=139–50 |year=2006 |month=November |pmid=16978917 |doi=10.1016/j.jcv.2006.08.013 |url=] or a factor in reactivation.cite journal |author=Klimas NG, Koneru AO |title=Chronic fatigue syndrome: inflammation, immune function, and neuroendocrine interactions |journal=Curr Rheumatol Rep |volume=9 |issue=6 |pages=482–7 |year=2007 |month=December |pmid=18177602 |doi= |url=] Other viruses implicated by some researchers include Ross river virus,cite journal |author=Hickie I, Davenport T, Wakefield D, "et al" |title=Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study |journal=BMJ |volume=333 |issue=7568 |pages=575 |year=2006 |pmid=16950834 |doi=10.1136/bmj.38933.585764.AE] Borna disease,cite journal |author=Kitani T, Kuratsune H, Fuke I, "et al" |title=Possible correlation between Borna disease virus infection and Japanese patients with chronic fatigue syndrome |journal=Microbiol. Immunol. |volume=40 |issue=6 |pages=459–62 |year=1996 |pmid=8839433 |doi=] Parvovirus B19,cite journal |author=Devanur LD, Kerr JR |title=Chronic fatigue syndrome |journal=J. Clin. Virol. |volume=37 |issue=3 |pages=139–50 |year=2006 |pmid=16978917 |doi=10.1016/j.jcv.2006.08.013] and herpes viruses Cytomegalovirus (HHV-5),cite journal |author=Beqaj SH, Lerner AM, Fitzgerald JT |title=Immunoassay with cytomegalovirus early antigens from gene products p52 and CM2 (UL44 and UL57) detect active infection in patients with chronic fatigue syndrome |journal=J Clin Pathol |volume= |issue= |pages= |year=2007 |pmid=18037660 |doi=10.1136/jcp.2007.050633] Human Herpesvirus Six (HHV-6), and HHV-7.cite journal |author=Chapenko S, Krumina A, Kozireva S, "et al" |title=Activation of human herpesviruses 6 and 7 in patients with chronic fatigue syndrome |journal=J. Clin. Virol. |volume=37 Suppl 1 |issue= |pages=S47–51 |year=2006 |pmid=17276369 |doi=10.1016/S1386-6532(06)70011-7] cite journal |author=De Bolle L, Naesens L, De Clercq E |title=Update on human herpesvirus 6 biology, clinical features, and therapy |journal=Clin. Microbiol. Rev. |volume=18 |issue=1 |pages=217–45 |year=2005 |pmid=15653828 |doi=10.1128/CMR.18.1.217-245.2005] A role for herpes viruses in CFS is controversial. [cite journal | author = | title = Chronic Fatigue Syndrome and Herpesviruses: the Fading Evidence. | journal = Herpes | volume = 7 | issue = 2 | pages = 46–50 | year = 2000 | pmid = 11867001] cite journal |author=Komaroff AL, Jacobson S, Ablashi DV, Yamanishi K |title=Highlights from 5th International Conference on HHV-6 and -7 |journal=Herpes |volume=13 |issue=3 |pages=81–2 |year=2006 |pmid=17147913 |doi=] cite journal |author=Komaroff AL |title=Is human herpesvirus-6 a trigger for chronic fatigue syndrome? |journal=J. Clin. Virol. |volume=37 Suppl 1 |issue= |pages=S39–46 |year=2006 |pmid=17276367 |doi=10.1016/S1386-6532(06)70010-5]

Several bacteria have been associated with some cases of CFS. Q Fever, caused by "Coxiella burnetii", can cause a post infectious fatigue syndrome resembling CFScite journal |author=Parker NR, Barralet JH, Bell AM |title=Q fever |journal=Lancet |volume=367 |issue=9511 |pages=679–88 |year=2006 |month=February |pmid=16503466 |doi=10.1016/S0140-6736(06)68266-4 |url=] cite journal |author=Devanur LD, Kerr JR |title=Chronic fatigue syndrome |journal=J. Clin. Virol. |volume=37 |issue=3 |pages=139–50 |year=2006 |month=November |pmid=16978917 |doi=10.1016/j.jcv.2006.08.013 |url=] cite journal |author=Madariaga MG, Rezai K, Trenholme GM, Weinstein RA |title=Q fever: a biological weapon in your backyard |journal=Lancet Infect Dis |volume=3 |issue=11 |pages=709–21 |year=2003 |month=November |pmid=14592601 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/S1473309903008041] CFS patients reportedly have higher rates of Chlamydia pneumoniae infection than controls.cite journal |author=Nicolson GL, Gan R, Haier J |title=Multiple co-infections (Mycoplasma, Chlamydia, human herpes virus-6) in blood of chronic fatigue syndrome patients: association with signs and symptoms |journal=APMIS |volume=111 |issue=5 |pages=557–66 |year=2003 |month=May |pmid=12887507 |doi= |url=http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0903-4641&date=2003&volume=111&issue=5&spage=557] cite journal |author=Devanur LD, Kerr JR |title=Chronic fatigue syndrome |journal=J. Clin. Virol. |volume=37 |issue=3 |pages=139–50 |year=2006 |month=November |pmid=16978917 |doi=10.1016/j.jcv.2006.08.013 |url=] The possible influence of Mycoplasma is disputed, with reports forcite journal |author=Nijs J, Nicolson GL, De Becker P, Coomans D, De Meirleir K |title=High prevalence of Mycoplasma infections among European chronic fatigue syndrome patients. Examination of four Mycoplasma species in blood of chronic fatigue syndrome patients |journal=FEMS Immunol. Med. Microbiol. |volume=34 |issue=3 |pages=209–14 |year=2002 |month=November |pmid=12423773 |doi= |url=http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0928-8244&date=2002&volume=34&issue=3&spage=209] cite journal |author=Nasralla M, Haier J, Nicolson GL |title=Multiple mycoplasmal infections detected in blood of patients with chronic fatigue syndrome and/or fibromyalgia syndrome |journal=Eur. J. Clin. Microbiol. Infect. Dis. |volume=18 |issue=12 |pages=859–65 |year=1999 |month=December |pmid=10691196 |doi= |url=http://link.springer.de/link/service/journals/10096/bibs/9018012/90180859.htm] cite journal |author=Choppa PC, Vojdani A, Tagle C, Andrin R, Magtoto L |title=Multiplex PCR for the detection of Mycoplasma fermentans, M. hominis and M. penetrans in cell cultures and blood samples of patients with chronic fatigue syndrome |journal=Mol. Cell. Probes |volume=12 |issue=5 |pages=301–8 |year=1998 |month=October |pmid=9778455 |doi=10.1006/mcpr.1998.0186 |url=] cite journal |author=Vojdani A, Choppa PC, Tagle C, Andrin R, Samimi B, Lapp CW |title=Detection of Mycoplasma genus and Mycoplasma fermentans by PCR in patients with Chronic Fatigue Syndrome |journal=FEMS Immunol. Med. Microbiol. |volume=22 |issue=4 |pages=355–65 |year=1998 |month=December |pmid=9879928 |doi= |url=http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0928-8244&date=1998&volume=22&issue=4&spage=355] and against.cite journal |author=Vernon SD, Shukla SK, Reeves WC |title=Absence of Mycoplasma species DNA in chronic fatigue syndrome |journal=J. Med. Microbiol. |volume=52 |issue=Pt 11 |pages=1027–8 |year=2003 |month=November |pmid=14532349 |doi= |url=http://jmm.sgmjournals.org/cgi/pmidlookup?view=long&pmid=14532349] A review concludes the role of Mycoplasma as causal agents, cofactors, or opportunistic infections is not clear.cite journal |author=Endresen GK |title=Mycoplasma blood infection in chronic fatigue and fibromyalgia syndromes |journal=Rheumatol. Int. |volume=23 |issue=5 |pages=211–5 |year=2003 |month=September |pmid=12879275 |doi=10.1007/s00296-003-0355-7 |url=] Gram-negative enterobacteria and increased intestinal permeability may be associated with severity of CFS symptoms.cite journal |author=Maes M, Mihaylova I, Leunis JC |title=Increased serum IgA and IgM against LPS of enterobacteria in chronic fatigue syndrome (CFS): indication for the involvement of gram-negative enterobacteria in the etiology of CFS and for the presence of an increased gut-intestinal permeability |journal=J Affect Disord |volume=99 |issue=1-3 |pages=237–40 |year=2007 |month=April |pmid=17007934 |doi=10.1016/j.jad.2006.08.021 |url=] Multiple bacterial and/or viral co-infections (Mycoplasma, Chlamydia, HHV-6) have been associated with increased severity of signs and symptoms.cite journal |author=Nicolson GL, Gan R, Haier J |title=Multiple co-infections (Mycoplasma, Chlamydia, human herpes virus-6) in blood of chronic fatigue syndrome patients: association with signs and symptoms |journal=APMIS |volume=111 |issue=5 |pages=557–66 |year=2003 |month=May |pmid=12887507 |doi= |url=http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0903-4641&date=2003&volume=111&issue=5&spage=557]

Immunological dysfunction

Immunological factors including a chronic activation or suppression of the immune system may contribute to symptoms of CFS,cite journal |author=Appel S, Chapman J, Shoenfeld Y |title=Infection and vaccination in chronic fatigue syndrome: myth or reality? |journal=Autoimmunity |volume=40 |issue=1 |pages=48–53 |year=2007 |pmid=17364497 |doi=10.1080/08916930701197273] but they may not represent the entire picturecite journal | author = Cho HJ, Skowera A, Cleare A, Wessely S | title = Chronic fatigue syndrome: an update focusing on phenomenology and pathophysiology. | journal = Curr Opin Psychiatry | volume = 19 | issue = 1 | pages = 67–73 | year = 2006 | pmid = 16612182 | doi = 10.1097/01.yco.0000194370.40062.b0] and some CFS experts doubt they are responsible.

Autoimmune disorders [Kennedy G, Spence V, Underwood C, Belch JJ. Increased neutrophil apoptosis in chronic fatigue syndrome.J Clin Pathol. 2004 Aug;57(8):891-3.] [Patarca R, Klimas NG, Lugtendorf S, Antoni M, Fletcher MA. Dysregulated expression of tumor necrosis factor in chronic fatigue syndrome: interrelations with cellular sources and patterns of soluble immune mediator expression. Clin Infect Dis. 1994 Jan;18 Suppl 1:S147-53.] and allergies or food intolerance [cite conference |first=Emms TM |last= |authorlink= |coauthors= Roberts TK, Butt HL, et al|title=Food Intolerance in Chronic Fatigue Syndrome |booktitle= |pages=Conference Paper 15 |publisher=American Association for Chronic Fatigue Syndrome |date=January 2001 |location=Seattle WA |url= |accessdate= |id= ] cite journal |author=Logan AC, Wong C |title=Chronic fatigue syndrome: oxidative stress and dietary modifications |journal=Alternative medicine review : a journal of clinical therapeutic |volume=6 |issue=5 |pages=450–9 |year=2001 |pmid=11703165 |doi=] have been reported in CFS sufferers. Gene expression changes have been reported in the white blood cells of CFS patients, consistent with the theory of immune system activation, [Original Research Paper, from the Journal of Clinical Pathology http://www.cfids.org/cfidslink/2005/cfs-gene.pdf] and abnormal types of antiviral protein RNase L are postulated to affect sleep-wake cycles and exercise capacity. [cite journal | author = Nijs J, De Meirleir K | title = Impairments of the 2-5A synthetase/RNase L pathway in chronic fatigue syndrome. | journal = In Vivo | volume = 19 | issue = 6 | pages = 1013–21 | year = 2005 | pmid = 16277015] High levels of Th2-type cytokines and the cells that make them are also found in CFScite journal |author=Patarca R |title=Cytokines and chronic fatigue syndrome |journal=Ann. N. Y. Acad. Sci. |volume=933 |issue= |pages=185–200 |year=2001 |pmid=12000020 |doi=] cite journal |author=Visser JT, De Kloet ER, Nagelkerken L |title=Altered glucocorticoid regulation of the immune response in the chronic fatigue syndrome |journal=Ann. N. Y. Acad. Sci. |volume=917 |issue= |pages=868–75 |year=2000 |pmid=11268418 |doi=] cite journal |author=Patarca-Montero R, Antoni M, Fletcher MA, Klimas NG |title=Cytokine and other immunologic markers in chronic fatigue syndrome and their relation to neuropsychological factors |journal=Appl Neuropsychol |volume=8 |issue=1 |pages=51–64 |year=2001 |pmid=11388124 |doi=] cite journal |author=Appel S, Chapman J, Shoenfeld Y |title=Infection and vaccination in chronic fatigue syndrome: myth or reality? |journal=Autoimmunity |volume=40 |issue=1 |pages=48–53 |year=2007 |pmid=17364497 |doi=10.1080/08916930701197273] . The resulting, increased antibody production may explain some immune dysfunctions in CFS. A reduction in the opposite Th1 response has also been reported,cite journal |author=Gaab J, Rohleder N, Heitz V, "et al" |title=Stress-induced changes in LPS-induced pro-inflammatory cytokine production in chronic fatigue syndrome |journal=Psychoneuroendocrinology |volume=30 |issue=2 |pages=188–98 |year=2005 |pmid=15471616 |doi=10.1016/j.psyneuen.2004.06.008] cite journal |author=Visser J, Blauw B, Hinloopen B, "et al" |title=CD4 T lymphocytes from patients with chronic fatigue syndrome have decreased interferon-gamma production and increased sensitivity to dexamethasone |journal=J. Infect. Dis. |volume=177 |issue=2 |pages=451–4 |year=1998 |pmid=9466535 |doi=] cite journal |author=Klimas NG, Salvato FR, Morgan R, Fletcher MA |title=Immunologic abnormalities in chronic fatigue syndrome |journal=J. Clin. Microbiol. |volume=28 |issue=6 |pages=1403–10 |year=1990 |pmid=2166084 |doi=] with implications for altered Th1/Th2 balance. Therapeutic alterations of cytokine expression patterns are being investigated.cite journal |author=Patarca R |title=Cytokines and chronic fatigue syndrome |journal=Ann. N. Y. Acad. Sci. |volume=933 |issue= |pages=185–200 |year=2001 |pmid=12000020 |doi=] cite journal |author=Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES |title=The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system |journal=Pharmacol. Rev. |volume=52 |issue=4 |pages=595–638 |year=2000 |pmid=11121511 |doi=]

In contrast, immunodeficiency disorders characterized by abnormal T-cell subset ratios, levels of immunoglobulins, and hypoallergic responses on the French Multitest have been reported in CFS.cite journal |author=Patarca R |title=Cytokines and chronic fatigue syndrome |journal=Ann. N. Y. Acad. Sci. |volume=933 |issue= |pages=185–200 |year=2001 |pmid=12000020 |doi=] Patients with lower natural killer cell activity report less vigor, more daytime dysfunction, and more cognitive impairment [cite journal | author = Siegel SD, Antoni MH, Fletcher MA, Maher K, Segota MC, Klimas N | title = Impaired natural immunity, cognitive dysfunction, and physical symptoms in patients with chronic fatigue syndrome: preliminary evidence for a subgroup? | journal = J Psychosom Res | volume = 60 | issue = 6 | pages = 559–66 | year = 2006 | pmid = 16731230 | doi = 10.1016/j.jpsychores.2006.03.001] There is also evidence that people with CFS have improper gene expression including both over expression and under expression of genes involved in the immune system (see the gene expression section).

Altered permeability of the blood-brain barrier (BBB) may contribute to ongoing signs and neurological symptoms found in CFS.cite journal |author=Bested AC, Saunders PR, Logan AC |title=Chronic fatigue syndrome: neurological findings may be related to blood--brain barrier permeability |journal=Med. Hypotheses |volume=57 |issue=2 |pages=231-7 |year=2001 |pmid=11461179 |doi=10.1054/mehy.2001.1306] The monocyte /macrophage, which crosses the blood brain barrier, is an essential candidate cell in the study of psychoneuroimmunology.cite journal |author=Fricchione G, Daly R, Rogers MP, Stefano GB |title=Neuroimmunologic influences in neuropsychiatric and psychophysiologic disorders |journal=Acta Pharmacol. Sin. |volume=22 |issue=7 |pages=577-87 |year=2001 |pmid=11749820 |doi=]

Endocrine system

In a 2006 update in the journal "Curr Opin Psychiatry" it was said; “Recent advances in understanding the pathophysiology of chronic fatigue syndrome continue to demonstrate the involvement of the central nervous system. Hyperserotonergic state and hypoactivity of the hypothalamic-pituitary-adrenal axis (HPA axis) constitute other findings, but the question of whether these alterations are a cause or consequence of chronic fatigue syndrome still remains unanswered.” cite journal |author=Cho HJ, Skowera A, Cleare A, Wessely S |title=Chronic fatigue syndrome: an update focusing on phenomenology and pathophysiology |journal=Curr Opin Psychiatry |volume=19 |issue=1 |pages=67–73 |year=2006 |pmid=16612182 |doi=10.1097/01.yco.0000194370.40062.b0] Alterations in serotonin signaling can lead to physiologic and behavioral changes. Polymorphisms in genes related to serotonin pathways may indicate genetic predisposition in the pathophysiology of CFS.cite journal |author=Smith AK, Dimulescu I, Falkenberg VR, "et al" |title=Genetic evaluation of the serotonergic system in chronic fatigue syndrome |journal=Psychoneuroendocrinology |volume=33 |issue=2 |pages=188–97 |year=2008 |pmid=18079067 |doi=10.1016/j.psyneuen.2007.11.001] Some researchers think cold therapy can increase serotonin levels to treat CFS.cite journal |author=Shevchuk NA |title=Possible use of repeated cold stress for reducing fatigue in chronic fatigue syndrome: a hypothesis |journal=Behav Brain Funct |volume=3 |issue= |pages=55 |year=2007 |pmid=17958903 |doi=10.1186/1744-9081-3-55]

Thyroid and adrenal disorders can cause CFS-like symptoms, as can several other known endocrine disorders. The hypothalamic-pituitary-adrenal axis (HPA axis) controls levels of hormones such as cortisol and is activated in a circadian rhythms and modulated by factors such as stress, digestion or illness. It is important in regulating energy metabolism, the immune system, stress responses and inflammation in the body. In CFS there is seen low cortisol,cite journal |author=Cleare AJ |title=The neuroendocrinology of chronic fatigue syndrome |journal=Endocr. Rev. |volume=24 |issue=2 |pages=236–52 |year=2003 |pmid=12700181 |doi=] enhanced sensitivity of the HPA axis to negative feedback,cite journal |author=Jerjes WK, Taylor NF, Wood PJ, Cleare AJ |title=Enhanced feedback sensitivity to prednisolone in chronic fatigue syndrome |journal=Psychoneuroendocrinology |volume=32 |issue=2 |pages=192–8 |year=2007 |month=February |pmid=17276605 |doi=10.1016/j.psyneuen.2006.12.005 |url=] cite journal |author=Van Den Eede F, Moorkens G, Hulstijn W, "et al" |title=Combined dexamethasone/corticotropin-releasing factor test in chronic fatigue syndrome |journal=Psychol Med |volume= |issue= |pages=1–11 |year=2007 |month=September |pmid=17803834 |doi=10.1017/S0033291707001444 |url=] and a possibly altered diurnal cortisol rhythm.cite journal |author=Nater UM, Youngblood LS, Jones JF, "et al" |title=Alterations in diurnal salivary cortisol rhythm in a population-based sample of cases with chronic fatigue syndrome |journal=Psychosom Med |volume=70 |issue=3 |pages=298–305 |year=2008 |month=April |pmid=18378875 |doi=10.1097/PSY.0b013e3181651025 |url=] These results may not apply in all CFS,cite journal |author=Jerjes WK, Taylor NF, Peters TJ, Wessely S, Cleare AJ |title=Urinary cortisol and cortisol metabolite excretion in chronic fatigue syndrome |journal=Psychosom Med |volume=68 |issue=4 |pages=578–82 |year=2006 |pmid=16868267 |doi=10.1097/01.psy.0000222358.01096.54 |url=] cite journal |author=Jerjes WK, Peters TJ, Taylor NF, Wood PJ, Wessely S, Cleare AJ |title=Diurnal excretion of urinary cortisol, cortisone, and cortisol metabolites in chronic fatigue syndrome |journal=J Psychosom Res |volume=60 |issue=2 |pages=145–53 |year=2006 |month=February |pmid=16439267 |doi=10.1016/j.jpsychores.2005.07.008 |url=] and the HPA axis abnormalities could be a cause or a result. Some researchers say they are a likely factor in symptom propagation in CFS.cite journal |author=Van Den Eede F, Moorkens G, Van Houdenhove B, Cosyns P, Claes SJ |title=Hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome |journal=Neuropsychobiology |volume=55 |issue=2 |pages=112–20 |year=2007 |pmid=17596739 |doi=10.1159/000104468]

Gene expression and polymorphisms

CFS-related abnormalities in gene expression have been studied, including by the CDC. [cite web | url = http://www.cdc.gov/ncidod/diseases/cfs/publications/molecular_epi.htm| title = Molecular Epidemiology Program | date = 2005-07-25 | publisher = National Center for Infectious Diseases] cite web | last = Reeves W | coauthors = Vernon S | title = Press Briefing on Chronic Fatigue Syndrome | publisher = Centers for Disease Control and Prevention | date = April 20, 2006 | url = http://www.cdc.gov/od/oc/media/transcripts/t060420.htm | format = HTM | accessdate = 2008-01-27] Changes in genes involved in transport (both vesicle-mediated and protein transport), [cite journal | author = Whistler T, Jones JF, Unger ER, Vernon SD | title = Exercise responsive genes measured in peripheral blood of women with chronic fatigue syndrome and matched control subjects. | journal = BMC Physiol | volume = 5 | issue = 1 | pages = 5 | year = 2005 | pmid = 15790422 | url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=15790422 | doi = 10.1186/1472-6793-5-5] metabolism, [cite journal | author = Whistler T, Unger ER, Nisenbaum R, Vernon SD | title = Integration of gene expression, clinical, and epidemiologic data to characterize Chronic Fatigue Syndrome. | journal = J Transl Med | volume = 1 | issue = 1 | pages = 10 | year = 2003 | pmid = 14641939 | doi = 10.1186/1479-5876-1-10] immune regulation, neuronal function, mitochondrial function, apoptosis, and other processes have been reported. [cite journal | author = Vernon SD, Unger ER, Dimulescu IM, Rajeevan M, Reeves WC | title = Utility of the blood for gene expression profiling and biomarker discovery in chronic fatigue syndrome. | journal = Dis Markers | volume = 18 | issue = 4 | pages = 193–9 | year = 2002 | pmid = 12590173] [cite journal | author = Kaushik N, Fear D, Richards SC, McDermott CR, Nuwaysir EF, Kellam P, Harrison TJ, Wilkinson RJ, Tyrrell DA, Holgate ST, Kerr JR | title = Gene expression in peripheral blood mononuclear cells from patients with chronic fatigue syndrome. | journal = J Clin Pathol | volume = 58 | issue = 8 | pages = 826–32 | year = 2005 | pmid = 16049284 | doi = 10.1136/jcp.2005.025718] [cite journal | author = Fang H, Xie Q, Boneva R, Fostel J, Perkins R, Tong W | title = Gene expression profile exploration of a large dataset on chronic fatigue syndrome. | journal = Pharmacogenomics | volume = 7 | issue = 3 | pages = 429–40 | year = 2006 | pmid = 16610953 | doi = 10.2217/14622416.7.3.429] The CDC has said these changes could be involved in CFS.cite web | last = Reeves W | coauthors = Vernon S | title = Press Briefing on Chronic Fatigue Syndrome | publisher = Centers for Disease Control and Prevention | date = April 20, 2006 | url = http://www.cdc.gov/od/oc/media/transcripts/t060420.htm | format = HTM | accessdate = 2008-01-27] Some of the symptoms of gene expression differences may be treatable with existing drugs. [ BBC News (28 May 2005) - [http://news.bbc.co.uk/2/hi/health/4580051.stm Scientists 'unlock ME genetics'] (study still in its early stages)] Some researchers think gene expression studies could make possible better categorization of CFScite journal |author=Kerr J, Burke B, Petty R, "et al" |title=Seven genomic subtypes of Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS/ME): a detailed analysis of gene networks and clinical phenotypes |journal=J Clin Pathol |volume= |issue= |pages= |year=2007 |pmid=18057078 |doi=10.1136/jcp.2007.053553] cite journal |author=Kerr JR, Petty R, Burke B, "et al" |title=Gene expression subtypes in patients with chronic fatigue syndrome/myalgic encephalomyelitis |journal=J. Infect. Dis. |volume=197 |issue=8 |pages=1171–84 |year=2008 |month=April |pmid=18462164 |doi=10.1086/533453 |url=] and even help with differential diagnosis.cite journal |author=Saiki T, Kawai T, Morita K, "et al" |title=Identification of Marker Genes for Differential Diagnosis of Chronic Fatigue Syndrome |journal=Mol. Med. |volume= |issue= |pages= |year=2008 |month=July |pmid=18596870 |pmc=2442021 |doi=10.2119/2007-00059.Saiki |url=]

Some researchers think genetic polymorphisms are predisposing factors for CFS.cite journal |author=Wyller VB |title=The chronic fatigue syndrome--an update |journal=Acta Neurol. Scand., Suppl. |volume=187 |issue= |pages=7-14 |year=2007 |pmid=17419822 |doi=10.1111/j.1600-0404.2007.00840.x] Polymorphism in biology occurs when two or more clearly different types exist in the same population of the same species. The risk of developing CFS may also be influenced by these small genetic differences in genes of the central nervous,cite journal |author=Smith AK, Dimulescu I, Falkenberg VR, "et al" |title=Genetic evaluation of the serotonergic system in chronic fatigue syndrome |journal=Psychoneuroendocrinology |volume=33 |issue=2 |pages=188–97 |year=2008 |pmid=18079067 |doi=10.1016/j.psyneuen.2007.11.001] [cite journal | author=Narita M, Nishigami N, Narita N, Yamaguti K, Okado N, Watanabe Y, Kuratsune H | title=Association between serotonin transporter gene polymorphism and chronic fatigue syndrome | journal=Biochem. Biophys. Res. Commun. | volume=311 | issue=2 | pages=264–6 | year=2003 | pmid=14592408 | doi=10.1016/j.bbrc.2003.09.207] endocrine, [cite journal | author=Goertzel BN, Pennachin C, de Souza Coelho L, Gurbaxani B, Maloney EM, Jones JF | title=Combinations of single nucleotide polymorphisms in neuroendocrine effector and receptor genes predict chronic fatigue syndrome | journal=Pharmacogenomics | volume=7 | issue=3 | pages=475–83 | year=2006 | pmid=16610957 | doi=10.2217/14622416.7.3.475] [cite journal | author=Smith AK, White PD, Aslakson E, Vollmer-Conna U, Rajeevan MS | title=Polymorphisms in genes regulating the HPA axis associated with empirically delineated classes of unexplained chronic fatigue | journal=Pharmacogenomics | volume=7 | issue=3 | pages=387–94 | year=2006 | pmid=16610949 | doi=10.2217/14622416.7.3.387] [cite journal | author=Torpy DJ, Bachmann AW, Gartside M, Grice JE, Harris JM, Clifton P, Easteal S, Jackson RV, Whitworth JA | title=Association between chronic fatigue syndrome and the corticosteroid-binding globulin gene ALA SER224 polymorphism | journal=Endocr. Res. | volume=30 | issue=3 | pages=417–29 | year=2004 | pmid=15554358 | doi=10.1081/ERC-200035599] immune, [cite journal | author=Kerr JR | title=Pathogenesis of parvovirus B19 infection: host gene variability, and possible means and effects of virus persistence | journal=J. Vet. Med. B Infect. Dis. Vet. Public Health | volume=52 | issue=7-8 | pages=335–9 | year=2005 | pmid=16316396] [cite journal | author=Carlo-Stella N, Badulli C, De Silvestri A, Bazzichi L, Martinetti M, Lorusso L, Bombardieri S, Salvaneschi L, Cuccia M | title=A first study of cytokine genomic polymorphisms in CFS: Positive association of TNF-857 and IFNgamma 874 rare alleles | journal=Clin. Exp. Rheumatol. | volume=24 | issue=2 | pages=179–82 | year=2006 | pmid=16762155] and/or cardiovascular systems. [cite journal | author=Vladutiu GD, Natelson BH | title=Association of medically unexplained fatigue with ACE insertion/deletion polymorphism in Gulf War veterans | journal=Muscle Nerve | volume=30 | issue=1 | pages=38–43 | year=2004 | pmid=15221876 | doi=10.1002/mus.20055] A review published in 2007 stated that certain genetic polymorphisms might be regarded as predisposing factors.cite journal | author = Wyller VB | title = The chronic fatigue syndrome - an update | journal = Acta Neurol Scand Suppl | volume = 187 | pages = 7–14 | year = 2007 | pmid = 17419822 | doi = 10.1111/j.1600-0404.2007.00840.x]

Other hypotheses

Oxidative stress

Oxidative stress, an imbalance between the production of reactive oxygen and a biological system's ability to readily detoxify the reactive intermediates or easily repair the resulting damage is consistant with CFS symptoms, especially relating to fatigue, pain and exercise intolerance. [cite journal | author = Nijs J, Meeus M, De Meirleir K | title = Chronic musculoskeletal pain in chronic fatigue syndrome: recent developments and therapeutic implications. | journal = Man Ther | volume = 11 | issue = 3 | pages = 187–91 | year = 2006 | pmid = 16781183 | doi = 10.1016/j.math.2006.03.008] Gene expression studies suggest a common link between oxidative stress, immune system dysfunction and potassium imbalance in CFS patients leading to impaired nerve balance, reflected in abnormal heart rate variability.cite journal |author=Broderick G, Craddock RC, Whistler T, Taylor R, Klimas N, Unger ER |title=Identifying illness parameters in fatiguing syndromes using classical projection methods |journal=Pharmacogenomics |volume=7 |issue=3 |pages=407–19 |year=2006 |pmid=16610951 |doi=10.2217/14622416.7.3.407]

Hypothesis of CFS in which either viral or bacterial infection induces one or more cytokines. These induce nitric oxide synthase (iNOS), leading to increased nitric oxide levels. Nitric oxide, in turn, reacts with superoxide radical to generate the potent oxidant peroxynitrite. Multiple amplification and positive feedback mechanisms are proposed by which once peroxynitrite levels are elevated, they tend to be sustained at a high level. Such a vicious cycle mechanism has been proposed to explain the etiology of CFS, FMS and MCS. Stressors, acting primarily through the nitric oxide product, peroxynitrite, are thought to initiate a complex vicious cycle mechanism, known as the NO/ONOO- cycle that is responsible for symptoms in chronic illness. The role of peroxynitrite in the NO/ONOO- cycle also implies that such uncoupling is part of the chronic phase cycle mechanism such that agents that lower uncoupling will be useful in treatment.cite journal |author=Pall ML |title=Nitric oxide synthase partial uncoupling as a key switching mechanism for the NO/ONOO- cycle |journal=Med. Hypotheses |volume=69 |issue=4 |pages=821-5 |year=2007 |pmid=17448611 |doi=10.1016/j.mehy.2007.01.070] cite journal |author=Pall ML |title=Elevated, sustained peroxynitrite levels as the cause of chronic fatigue syndrome |journal=Med. Hypotheses |volume=54 |issue=1 |pages=115-25 |year=2000 |pmid=10790736 |doi=10.1054/mehy.1998.0825] cite journal |author=Pall ML, Satterlee JD |title=Elevated nitric oxide/peroxynitrite mechanism for the common etiology of multiple chemical sensitivity, chronic fatigue syndrome, and posttraumatic stress disorder |journal=Ann. N. Y. Acad. Sci. |volume=933 |issue= |pages=323-9 |year=2001 |pmid=12000033 |doi=] cite journal |author=Pall ML |title=Common etiology of posttraumatic stress disorder, fibromyalgia, chronic fatigue syndrome and multiple chemical sensitivity via elevated nitric oxide/peroxynitrite |journal=Med. Hypotheses |volume=57 |issue=2 |pages=139-45 |year=2001 |pmid=11461161 |doi=10.1054/mehy.2001.1325]

The role of oxidative stress in CFS is an emerging focus of research due to evidence of its association with some pathological features of this syndrome. New data collectively supports the presence of specific critical points in the muscle membranes that are affected by free radicals and in view of these considerations, the possible role of skeletal muscle oxidative imbalance in CFS is considered. cite journal |author=Fulle S, Pietrangelo T, Mancinelli R, Saggini R, Fanò G |title=Specific correlations between muscle oxidative stress and chronic fatigue syndrome: a working hypothesis |journal=J. Muscle Res. Cell. Motil. |volume=28 |issue=6 |pages=355-362 |year=2007 |pmid=18274865 |doi=10.1007/s10974-008-9128-y] The oxidative stress induced muscle membrane modifications may be related to alteration of membrane fluidity with deregulation of pump activities, sodium / potassium (Na(+)/K(+) and calcium (Ca(2+)-ATPase). cite journal |author=Fulle S, Belia S, Vecchiet J, Morabito C, Vecchiet L, Fanò G |title=Modification of the functional capacity of sarcoplasmic reticulum membranes in patients suffering from chronic fatigue syndrome |journal=Neuromuscul. Disord. |volume=13 |issue=6 |pages=479-84 |year=2003 |pmid=12899875 |doi=]

Selective n-6 fatty acid depletion suggest that oxidative stress and more specifically lipid peroxidation might play a role in CFS pathogenesis. The results of a study indicate that patients with CFS have increased susceptibility to peroxidation and that this is related both to their lower levels of serum transferrin and to other unidentified pro-oxidising effects of CFS. cite journal |author=Manuel y Keenoy B, Moorkens G, Vertommen J, De Leeuw I |title=Antioxidant status and lipoprotein peroxidation in chronic fatigue syndrome |journal=Life Sci. |volume=68 |issue=17 |pages=2037-49 |year=2001 |pmid=11388705 |doi=]

Evidence is put forward to suggest that myalgic encephalomyelitis, also known as chronic fatigue syndrome, may be associated with persistent viral infection. In turn, such infections are likely to impair the ability of the body to biosynthesise n-3 and n-6 long-chain polyunsaturated fatty acids by inhibiting the delta-6 desaturation of the precursor essential fatty acids--namely, alpha-linolenic acid and linoleic acid. This would, in turn, impair the proper functioning of cell membranes.cite journal |author=Puri BK |title=Long-chain polyunsaturated fatty acids and the pathophysiology of myalgic encephalomyelitis (chronic fatigue syndrome) |journal=J. Clin. Pathol. |volume=60 |issue=2 |pages=122-4 |year=2007 |pmid=16935966 |doi=10.1136/jcp.2006.042424] Alternatively oxidative stress might reduce essential fatty acids in membranes of chronic fatigue syndrome patients. cite journal |author=Nijs J, De Meirleir K |title=Oxidative stress might reduce essential fatty acids in erythrocyte membranes of chronic fatigue syndrome patients |journal=Nutr Neurosci |volume=7 |issue=4 |pages=251-3 |year=2004 |pmid=15682653 |doi=] cite journal |author=Liu Z, Wang D, Xue Q, "et al" |title=Determination of fatty acid levels in erythrocyte membranes of patients with chronic fatigue syndrome |journal=Nutr Neurosci |volume=6 |issue=6 |pages=389-92 |year=2003 |pmid=14744043 |doi=]

Several papers explain that depletion of essential fatty acids can result from an immune hyper-response, mediated either by immuno-globulins, by sustained cytokines, and/or by reduced lipo-cortin control (due to HPA hypo function) or by excessive metabolic mobilization of essential fatty acids. Oxygenases are suppressed in normal tissues but are activated by lipid hydroperoxides. Hydroperoxides are needed as activators to sustain production but one immediate product of fatty acid oxygenase action is lipid hydroperoxide. Positive feeback amplifies the peroxide in vicinity to the oxygenase, leading to free radical generation, oxidative stress and substrate depletion; the result of sustained extracellular signalling and intracellular amplification. cite journal |author=Gray JB, Martinovic AM |title=Eicosanoids and essential fatty acid modulation in chronic disease and the chronic fatigue syndrome |journal=Med. Hypotheses |volume=43 |issue=1 |pages=31-42 |year=1994 |pmid=7968718 |doi=] cite journal |author=Lands WE |title=Biochemical and cellular actions of membrane lipids |journal=Am. Rev. Respir. Dis. |volume=136 |issue=1 |pages=200-4 |year=1987 |pmid=3111318 |doi=]

Hypothesis that changes in ratio of essential fatty acid metabolites are the normal physiological responses to stressors, but when stressors are excessive or prolonged, systems may become unpredictably hypo-responsive after sustained hyper responses owing to factors such as receptor down regulation and substrate depletion. In time, many homeostatic systems become deranged and vicious circles held in that state by minor stressors. cite journal |author=Gray JB, Martinovic AM |title=Eicosanoids and essential fatty acid modulation in chronic disease and the chronic fatigue syndrome |journal=Med. Hypotheses |volume=43 |issue=1 |pages=31-42 |year=1994 |pmid=7968718 |doi=]

The inducible enzymes cyclo-oxygenase (COX-2) and inducible NO synthase (iNOS) have been found raised in CFS patients associated with symptoms and provides evidence to support hypotheses that CFS is accompanied by increased oxidative stress and inflammation. cite journal |author=Maes M, Mihaylova I, Kubera M, Bosmans E |title=Not in the mind but in the cell: increased production of cyclo-oxygenase-2 and inducible NO synthase in chronic fatigue syndrome |journal=Neuro Endocrinol. Lett. |volume=28 |issue=4 |pages=463-9 |year=2007 |pmid=17693978 |doi=]

Metabolic disorders

Metabolic disorders and mitochondrial disorders can cause symptoms that resemble CFS.cite journal |author=van de Glind G, de Vries M, Rodenburg R, Hol F, Smeitink J, Morava E |title=Resting muscle pain as the first clinical symptom in children carrying the MTTK A8344G mutation |journal=Eur. J. Paediatr. Neurol. |volume=11 |issue=4 |pages=243–6 |year=2007 |pmid=17293137 |doi=10.1016/j.ejpn.2007.01.004] Mitochondrial disturbances have been discovered in patients diagnosed with postviral fatigue syndrome.cite journal |author=Behan WM, More IA, Behan PO |title=Mitochondrial abnormalities in the postviral fatigue syndrome |journal=Acta Neuropathol. |volume=83 |issue=1 |pages=61–5 |year=1991 |pmid=1792865 |doi=] Folate deficiency may also mimic CFS symptoms. [cite journal |author=Lundell K, Qazi S, Eddy L, Uckun FM |title=Clinical activity of folinic acid in patients with chronic fatigue syndrome |journal=Arzneimittelforschung |volume=56 |issue=6 |pages=399–404 |year=2006 |pmid=16889122 |doi= |url=] [cite journal |author=Jacobson W, Saich T, Borysiewicz LK, Behan WM, Behan PO, Wreghitt TG |title=Serum folate and chronic fatigue syndrome |journal=Neurology |volume=43 |issue=12 |pages=2645–7 |year=1993 |month=December |pmid=8255470 |doi= |url=]

Essential fatty acid deficiencies

Essential fatty acid levels: Several studies published between 1990 a 2005 reported finding reduced levels of Omega-6 or Omega-3 essential fatty acids in cell membranes or serum in patients diagnosed with postviral fatigue syndrome or CDC defined CFS.cite book |author=Horrobin, David F. |title=Omega-6 essential fatty acids: pathophysiology and roles in clinical medicine |publisher=Wiley-Liss |location= New York |year=1990 |pages=275-282 |isbn=0-471-56693-4 |oclc= |doi=] cite journal |author=Behan PO, Behan WM, Horrobin D |title=Effect of high doses of essential fatty acids on the postviral fatigue syndrome |journal=Acta Neurol. Scand. |volume=82 |issue=3 |pages=209–16 |year=1990 |pmid=2270749 |doi=] cite journal |author=Ogawa R, Toyama S, Matsumoto H. |title=Chronic fatigue syndrome--cases in the Kanebo Memorial Hospital |journal=Nippon Rinsho. |volume=50 |issue=11 |pages=2648–52|year=1992 |pmid=1337561 |doi=] cite journal |author=Liu Z, Wang D, Xue Q, "et al" |title=Determination of fatty acid levels in erythrocyte membranes of patients with chronic fatigue syndrome |journal=Nutritional neuroscience |volume=6 |issue=6 |pages=389–92 |year=2003 |pmid=14744043 |doi=] cite journal |author=Maes M, Mihaylova I, Leunis JC |title=In chronic fatigue syndrome, the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation |journal=Neuro Endocrinol. Lett. |volume=26 |issue=6 |pages=745–51 |year=2005 |pmid=16380690 |doi=] One study conducted in 1999 on Oxford criteria defined CFS patients (Warren et al.) found no significant differences in fatty acid levels between treatment and placebo groups.cite journal |author=Warren G, McKendrick M, Peet M |title=The role of essential fatty acids in chronic fatigue syndrome. A case-controlled study of red-cell membrane essential fatty acids (EFA) and a placebo-controlled treatment study with high dose of EFA |journal=Acta Neurol. Scand. |volume=99 |issue=2 |pages=112–6 |year=1999 |pmid=10071170 |doi=] There have also been two controlled systematic proton neurospectroscopy studies of CFS patients that found raised levels of choline in brain areas consistent with an abnormality of essential fatty acid and phospholipid metabolism in the brain in CFS patients.cite journal |author=Puri BK |title=Long-chain polyunsaturated fatty acids and the pathophysiology of myalgic encephalomyelitis (chronic fatigue syndrome) |journal=J. Clin. Pathol. |volume=60 |issue=2 |pages=122–4 |year=2007 |pmid=16935966 |doi=10.1136/jcp.2006.042424] cite journal |author=Puri BK |title=The use of eicosapentaenoic acid in the treatment of chronic fatigue syndrome |journal=Prostaglandins Leukot. Essent. Fatty Acids |volume=70 |issue=4 |pages=399–401 |year=2004 |pmid=15041033 |doi=10.1016/j.plefa.2003.12.015] These changes have been considered due to essential fatty acid deficiencies resulting from delta 6 desaturase (D6D) enzyme inhibition in CFS. Some researchers have suggested D6D inhibition is linked to a possible viral cause.cite journal |author=Puri BK |title=Long-chain polyunsaturated fatty acids and the pathophysiology of myalgic encephalomyelitis (chronic fatigue syndrome) |journal=J. Clin. Pathol. |volume=60 |issue=2 |pages=122–4 |year=2007 |pmid=16935966 |doi=10.1136/jcp.2006.042424] cite journal |author=Puri BK |title=The use of eicosapentaenoic acid in the treatment of chronic fatigue syndrome |journal=Prostaglandins Leukot. Essent. Fatty Acids |volume=70 |issue=4 |pages=399–401 |year=2004 |pmid=15041033 |doi=10.1016/j.plefa.2003.12.015] [cite journal |last=Carruthers |first=BM |authorlink= |coauthors=Jain AK et. al. |year=2003 |month= |title=Myalgic Encephomyelitis / Chronic fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols (a Consensus Document) |journal=Journal of Chronic Fatigue Syndrome |volume=11 |issue=1 |pages=66 |id= |url= |accessdate= |quote= ] However, researchers at an Australian University of Newcastle who reported finding, in CDC criteria defined CFS patients; a dysregulation in D6D enzyme activity and fatty acid changes consistent with an inflammatory mediated event. Found that both gradual and sudden onset had the same fatty acid anomaly differentiaiting them from controls, the primary lipid changes were potentially non-viral induced. Whilst sudden onset CFS patients could be differentiated by a key post-viral modification to fatty acids. [ McGregor N.R. Dunstan H.R. et al. 1998 “Alterations in Plasma Lipid Composition in Patients with CFS” presented at Conference; The Clinical and Scientific Basis of CFS, Sydney 1998, P38 ] [ McGregor N.R. Dunstan H.R. et al. 1998 “Assessment of Lipid Homeostasis in Sudden and Gradual Onset CFS Patients” presented at Conference; The Clinical and Scientific Basis of CFS, Sydney 1998, P39 ] Other studies have shown that altered ratios of fatty acids and decreased availability of omega-3 EFAs plays a role in CFS symptoms and severity and is related to findings of lowered zinc and immune dysfunction, including the lowered mitogen-stimulated activation of some T cells. The decreased cell markers are also indicators of increased inflammation and low natural killer cell activation.cite journal |author=Maes M, Mihaylova I, Leunis JC |title=In chronic fatigue syndrome, the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation |journal=Neuro Endocrinol. Lett. |volume=26 |issue=6 |pages=745–51 |year=2005 |pmid=16380690 |doi=] cite journal |author=Mihaylova I, DeRuyter M, Rummens JL, Bosmans E, Maes M |title=Decreased expression of CD69 in chronic fatigue syndrome in relation to inflammatory markers: evidence for a severe disorder in the early activation of T lymphocytes and natural killer cells |journal=Neuro Endocrinol. Lett. |volume=28 |issue=4 |pages=477–83 |year=2007 |pmid=17693977 |doi=] The reduced EFA findings are considered indicative of; oxidative stress with reduced anti-oxidant status, cite journal |author=Liu Z, Wang D, Xue Q, "et al" |title=Determination of fatty acid levels in erythrocyte membranes of patients with chronic fatigue syndrome |journal=Nutr Neurosci |volume=6 |issue=6 |pages=389–92 |year=2003 |pmid=14744043 |doi=] cite journal |author=Fulle S, Mecocci P, Fanó G, "et al" |title=Specific oxidative alterations in vastus lateralis muscle of patients with the diagnosis of chronic fatigue syndrome |journal=Free Radic. Biol. Med. |volume=29 |issue=12 |pages=1252–9 |year=2000 |pmid=11118815 |doi=] cite journal |author=Kennedy G, Spence VA, McLaren M, Hill A, Underwood C, Belch JJ |title=Oxidative stress levels are raised in chronic fatigue syndrome and are associated with clinical symptoms |journal=Free Radic. Biol. Med. |volume=39 |issue=5 |pages=584–9 |year=2005 |pmid=16085177 |doi=10.1016/j.freeradbiomed.2005.04.020] cite journal |author=Richards RS, Roberts TK, McGregor NR, Dunstan RH, Butt HL |title=Blood parameters indicative of oxidative stress are associated with symptom expression in chronic fatigue syndrome |journal=Redox Rep. |volume=5 |issue=1 |pages=35–41 |year=2000 |pmid=10905542 |doi=]

Carnitine deficiency may produce symptoms of fatigue and myalgia,cite book |author=Jenkins, Rachel; Mowbray, James F. |title=Post-viral fatigue syndrome (Myalgic encephalomyelitis) |publisher=Wiley |location=New York |year=1991 |Chapter= Essential fatty acids and post viral fatigue syndrome, Author; Horribin DF, pp 393-404 |isbn=0-471-92846-1 |oclc= |doi=] cite journal |author=Kuratsune H, Yamaguti K, Takahashi M, Misaki H, Tagawa S, Kitani T |title=Acylcarnitine deficiency in chronic fatigue syndrome |journal=Clin. Infect. Dis. |volume=18 Suppl 1 |issue= |pages=S62–7 |year=1994 |pmid=8148455 |doi=] and low serum total carnitine, free carnitine and acylcarnitine levels have been reported in CFS.cite journal |author=Plioplys AV, Plioplys S |title=Serum levels of carnitine in chronic fatigue syndrome: clinical correlates |journal=Neuropsychobiology |volume=32 |issue=3 |pages=132–8 |year=1995 |pmid=8544970 |doi=] cite journal |author=Kuratsune H, Yamaguti K, Lindh G, "et al" |title=Low levels of serum acylcarnitine in chronic fatigue syndrome and chronic hepatitis type C, but not seen in other diseases |journal=Int. J. Mol. Med. |volume=2 |issue=1 |pages=51–6 |year=1998 |pmid=9854142 |doi=] cite journal |author=Kuratsune H, Yamaguti K, Takahashi M, Misaki H, Tagawa S, Kitani T |title=Acylcarnitine deficiency in chronic fatigue syndrome |journal=Clin. Infect. Dis. |volume=18 Suppl 1 |issue= |pages=S62–7 |year=1994 |pmid=8148455 |doi=] Biosynthesis of neurotransmitters through acetylcarnitine might be reduced in some brain regions of CFS patients.cite journal |author=Kuratsune H, Yamaguti K, Lindh G, "et al" |title=Brain regions involved in fatigue sensation: reduced acetylcarnitine uptake into the brain |journal=Neuroimage |volume=17 |issue=3 |pages=1256–65 |year=2002 |pmid=12414265 |doi=] Others report of finding reduced levels of carnitine together with reduced essential fatty acids in patients with CDC defined CFS.cite journal |author=Jones MG, Goodwin CS, Amjad S, Chalmers RA |title=Plasma and urinary carnitine and acylcarnitines in chronic fatigue syndrome |journal=Clin. Chim. Acta |volume=360 |issue=1-2 |pages=173–7 |year=2005 |pmid=15967423 |doi=10.1016/j.cccn.2005.04.029] A gene expression study indicates altered carnitine function, mitochondrial function, and fatty acid metabolism in post-infective fatigue.cite journal |author=Vernon SD, Whistler T, Cameron B, Hickie IB, Reeves WC, Lloyd A |title=Preliminary evidence of mitochondrial dysfunction associated with post-infective fatigue after acute infection with Epstein Barr virus |journal=BMC Infect. Dis. |volume=6 |issue= |pages=15 |year=2006 |pmid=16448567 |doi=10.1186/1471-2334-6-15]

Toxic agents

Insecticides have a possible effect on the cause and/or course of CFS.cite journal |author=Devanur LD, Kerr JR |title=Chronic fatigue syndrome |journal=J. Clin. Virol. |volume=37 |issue=3 |pages=139–50 |year=2006 |pmid=16978917 |doi=10.1016/j.jcv.2006.08.013]

Exercise findings

Childhood exercise and adult risk of CFS are inversely correlated in a large study finding the development of CFS was not associated with other childhood or maternal factors such as psychological problems, academic ability, allergic tendencies, birth weight, birth order or obesity. [cite journal | author = Viner R, Hotopf M | title = Childhood predictors of self reported chronic fatigue syndrome/myalgic encephalomyelitis in adults: national birth cohort study. | journal = BMJ | volume = 329 | issue = 7472 | pages = 941 | year = 2003 | pmid = 15469945 | doi = 10.1136/bmj.38258.507928.55]

Abnormal lactic acid responses to exercise in some CFS patientscite journal |author=Lane RJ, Barrett MC, Taylor DJ, Kemp GJ, Lodi R |title=Heterogeneity in chronic fatigue syndrome: evidence from magnetic resonance spectroscopy of muscle |journal=Neuromuscul. Disord. |volume=8 |issue=3-4 |pages=204–9 |year=1998 |pmid=9631403 |doi=] cite journal |author=Lane RJ, Barrett MC, Woodrow D, Moss J, Fletcher R, Archard LC |title=Muscle fibre characteristics and lactate responses to exercise in chronic fatigue syndrome |journal=J. Neurol. Neurosurg. Psychiatr. |volume=64 |issue=3 |pages=362–7 |year=1998 |pmid=9527150 |doi=] cite journal |author=Lane RJ, Soteriou BA, Zhang H, Archard LC |title=Enterovirus related metabolic myopathy: a postviral fatigue syndrome |journal=J. Neurol. Neurosurg. Psychiatr. |volume=74 |issue=10 |pages=1382–6 |year=2003 |pmid=14570830 |doi=] have been suggested to be a factor in CFS because it is commonly believed to be responsible for muscle fatigue.cite journal |author=Lamb GD, Stephenson DG |title=Point: lactic acid accumulation is an advantage during muscle activity |journal=J. Appl. Physiol. |volume=100 |issue=4 |pages=1410–2; discussion 1414 |year=2006 |pmid=16540714 |doi=10.1152/japplphysiol.00023.2006] However, some scientists have found that lactic acid may actually help prevent muscle fatigue rather than cause it, by keeping muscles properly responding to nerve signals. [cite journal | author = Pedersen TH, Nielsen OB, Lamb GD, Stephenson DG | title = Intracellular acidosis enhances the excitability of working muscle. | journal = Science | volume = 305 | issue = 5687 | pages = 1144–7 | year = 2004 | pmid = 15326352 | doi = 10.1126/science.1101141]

Other findings

Children and teenagers with CFS are several times more likely than healthy controls to have some hyperflexible joints [cite journal | author = Barron DF, Cohen BA, Geraghty MT, Violand R, Rowe PC | title = Joint hypermobility is more common in children with chronic fatigue syndrome than in healthy controls. | journal = J Pediatr | volume = 141 | issue = 3 | pages = 421–5 | year = 2002 | pmid = 12219066 | doi = 10.1067/mpd.2002.127496] in an association with Ehlers-Danlos syndrome.

References